1. Update on Atazanavir and the Early Access Program AIDS Treatment Activists Coalition Seattle, Washington February 24 2001

2. Atazanavir Profile n Azapeptide inhibitor of HIV protease n Dosed 400 mg QD with food (2 capsules) n Favorable potency and resistance profile n Superior lipid profile to NFV or RTV/SQV n Safety, efficacy, tolerability demonstrated in Phase II Studies l Rapidly, durably suppresses HIV RNA l Durably increases CD4 count

3. Atazanavir: Antiviral Properties n Azapeptide inhibitor of HIV protease n Potent activity in vitro 2–19 times more potent than available PIs IC 50 2–5 nM IC 90 8–12 nM n Demonstrated potency in vivo 1.5 log decline in HIV RNA n Favorable resistance profile in vitro

4. Dose Selection: Probability of 1.5 Log Δ in HIV RNA by Week 2 Supports 400 mg Dose 200 400 ) 500 N=22 N=13 N=21 Mean values: 200 mg QD 400 mg QD 500 mg QD

5. Gong. Antimicrob Agents Chemother 2000;44:2319. Atazanavir Sensitivity Clinical Isolates n Atazanavir displays a distinct sensitivity profile against a large panel of resistant isolates —Sensitivity retained against 71 of 74 (96%) isolates resistant to 1 to 2 PIs —Reduced sensitivity to atazanavir observed against isolates resistant to 4 or 5 PIs n Multiple amino acid substitutions required to significantly lose sensitivity

6. Atazanavir: PK Properties n Favorable oral bioavailability (> 50%) n Increased absorption in fed state n Prolonged t1/2 - comfortable Cmin cushion over IC50 n Distributes widely (CSF, semen) n Metabolized via CYP3A4 Ki =2.2  M, versus ritonavir (Ki =0.1  M), indinavir (Ki =0.4  M)

7. CMIN=220+184 ng/mL CMIN=133+101 ng/mL CMIN=33+20 ng/mL CMIN=19+16 ng/mL Effect of a Light Meal upon Steady- State PK at 200 and 400 mg QD N=14 N=6 N=14 N=6

8. Drug-Drug Interaction Studies: Completed with dosing implications

9. PK Data: ATV/RTV

10. PK Data: ATV (300 mg) +/- RTV

11. Drug-Drug Interaction Studies: Completed with dosing implications

12. Hyperbilirubinemia: Bilirubin Physiology * ICT = Intracellular transport

13. 0 10 20 30 40 50 60 70 ATV 200 mgATV 400 mgATV 500 mgATV 600 mg Atazanavir Bilirubin Elevations Events (%) Seven patients discontinued for bilirubin elevations Grade 3-4 = > 2.5 x ULN Dose reductions for grade 4 = > 5 x ULN Treated (N)102279107195 0% 15% 12% 24% - data from AI424-007/008

14. Hyperbilirubinemia: Relationship to dose and reversibility (Light meal)

15. Hyperbilirubinemia: Conclusions n Unconjugated hyperbilirubinemia, 40% n Scleral icterus, 5-10% n Without clinical significance - asymptomatic - without effect on liver enzymes - no effect on virologic/CD4 response n Rapidly reversible with drug interruption

16. Electrocardiogram Changes n Observations - dose dependent asymptomatic increases in QTc and PR intervals n Safety analyses - preclinical (ion channels, HERG) - clinical (ECGs, drug-drug effects)

18. ECG Signal

19. Naive Experienced Salvage Nelfinavir -037 (NFV) -007, -008 (NFV) -034 (EFV) Efavirenz Atazanavir Clinical Program -009 (RTV/SQV) -043 (LOP/R) -900 (EAP) -045 + RTV

20. AI424-007 (Stage I n = 98, Stage II n = 322) Treatment-Naive ATV 200, 400 or 500 mg QD vs + ddI + d4T NFV 750 mg TID 2 weeks monotherapy ATV 400 or 600 mg QD vs + d4T + 3TC NFV 1250 mg BID AI424-008 (n = 467) Treatment-Naive ATV 400/600mg QD + SQV 1200 mg QD2 NRTIs vs + (sensitive) RTV 400mg BID + SQV 400 mg BID AI424-009 (n = 85) Treatment-Experienced Atazanavir Phase II Studies

21. 0.0 B/L 16484 208 12 40 44 3224 28 36 Week –2.0 –3.0 –1.0 –0.5 –1.5 –2.5 Change (log 10 c/mL,  SE) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) Sanne. ICAAC; 2001. Study 008: Atazanavir vs Nelfinavir HIV RNA Median Change From Baseline

22. Study 008: Atazanavir vs Nelfinavir Treatment Response at 48 Weeks (ITT) LOQ = 400 c/mL 100 B/L 16484 208 12 40 443224 28 36 Week 0 60 80 40 20 Subjects (%) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) LOQ = 50 c/mL Sanne. ICAAC; 2001.

23. Study 008: Atazanavir vs Nelfinavir Treatment Response (As Treated) Week Subjects (%) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) *P<0.05, atazanavir vs nelfinavir. Sanne. ICAAC; 2001. LOQ = 400 c/mL 400 c/mL 100 B/L 16484 208 12 40 44 3224 28 36 0 60 80 40 20 LOQ = 50 c/mL 50 c/mL *

24. Study 008: Atazanavir vs Nelfinavir CD4 Median Change From Baseline 300 B/L 16484 208 12 40 443224 28 36 Week 100 0 200 250 150 50 CD4 (cells/mm 3,  SE) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) Sanne. ICAAC; 2001.

25. Study 008: Atazanavir vs Nelfinavir Clinical Adverse Events* at 48 Weeks Diarrhea 36 (20) † 29 (15) † 51 (56) Infection 75 (42)107 (55)44 (48) Headache 45 (25) 52 (27)24 (26) Pain (abdomen) 33 (19) 43 (22)12 (13) Periph neuro symptoms 32 (18) 42 (22)19 (21) Rash 39 (22) 34 (17)17 (19) Nausea 38 (21) 35 (18)16 (18) Atazanavir 400 mg600 mg Nelfinavir (n = 178)(n = 195)(n = 91) *Grade 1-4, reported with a frequency of >20% in any treatment group. † P<0.0001, atazanavir 400 mg and 600 mg vs nelfinavir. Sanne. ICAAC; 2001.

26. Study 009: ATV/SQV vs RTV/SQV in Subjects With Prior Failure Previous ARV Therapy ATV 400 mg 600 mg NFV (n = 32) (n = 27) (n = 23) Any PI28 (88) 23 (85) 20 (87) IDV16 (50) 7 (26) 5 (22) NFV12 (38) 18 (67) 15 (65) RTV 1 (3) 1 (4) 1 (4) SQV3 (9) 0 0 Any NNRTI6 (19) 6 (22)7 (30) DLV0 0 1 (4) EFV2 (6) 1 (4) 3 (13) NVP4 (13)4 (15)4 (17) Emivirine0 1 (4) 0 Haas. ICAAC; 2001.

27. Group: Number at risk Atazanavir 400:34303030292929 Atazanavir 600: 28232422232022 Ritonavir:23202017181413 –0.5 –1.5 0.0 Change (  SE) –2.0 –1.0 B/L4812162024 Week Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA: Mean Change From Baseline ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) Haas. ICAAC; 2001.

28. Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA Response (>1.0 log 10 or LOQ = 50 c/mL) B/L4 8 12 16 2024 Week 60 80 100 20 Responders (%) 0 40 ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) Haas. ICAAC; 2001.

29. Study 009: ATV/SQV vs RTV/SQV in Subjects With Prior Failure CD4 Median (SE) Cell Count 400 500 550 B/L 350 600 650 450 300 CD4 250 Week 4812162024 Haas. ICAAC; 2001. ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) Group: Number at risk ATV 400:34303031282829 ATV 600: 28242523232122 RTV:23192018181513

30. AI424-009 Total CholesterolTriglycerides Group: Number at risk Atazanavir 400:32313030282827 Atazanavir 600: 27242421211920 Ritonavir:23202017171513 Mean change (%) B/L4812162024 Week Atazanavir 400 mg (n = 32) Atazanavir 600 mg (n = 27) Ritonavir (n = 23)–5 10 15 –10 20 25 –15 –20 0 5 Group: Number at risk 27202219191715 22141312 91013 18121010 9 9 8 30 0 210 –30 –60 60 B/L4812162024 Week 180 150 120 90 Total Cholesterol and Triglycerides at 24 Weeks Atazanavir 400 mg (n = 32) Atazanavir 600 mg (n = 27) Ritonavir (n = 23)

31. Treatment ExperiencedTreatment Naive Phase III overview 1st treatment2nd treatmentHeavily experienced AI424-034 vs efavirenz AI424-037 vs nelfinavir in non PI failuresAI424-045 with tenofovir vs lopinavir/r in > 2 failure AI424-043 vs lopinavir/r in PI failures

32. Atazanavir General Goals for Phase III n Compare efficacy to EFV in ARV-naive population n Compare safety, tolerability and efficacy vs LPV/RTV in PI-failure population n Assess role in highly treatment experienced population when combined with RTV and tenofovir

33. Atazanavir Phase III Study 034 n Double blind, double dummy, randomized n N = 810 naive subjects, powered for % <LOQ n EFV vs Atazanavir: AZT + 3TC as NRTI n Metabolic endpoints —Insulin, C-peptide —DEXA, CT —Fasting Lipids n Assessment of reduction in CV risk

34. Atazanavir Phase III Study 037 n Double blind, double dummy, randomized n N = 400 PI-naive subjects, NRTI-experienced powered for % <LOQ n Atazanavir vs NFV: genotype to select NRTI n Metabolic endpoints —Insulin, C-peptide —DEXA, CT —Fasting Lipids n Assessment of reduction in CV risk

35. Atazanavir Phase II/III Study 043 n Open label, randomized, for PI-failure, n = 200 n Atazanavir vs LPV/RTV genotype to select NRTI n Metabolic endpoints insulin, C-peptide, LDL, T-Chol, HDL, TG n Assessment of CV risk reduction n QOL assessments

36. Atazanavir Phase II/III Study 045 n Open-label, randomized, comparative study n 3-class, 2-regimen failure n 3-arm —ATV/RTV + tenofovir and NRTI —ATV/SQV + tenofovir and NRTI —LPV/RTV + tenofovir and NRTI n 2 week single substitution n Assess HIV RNA and lipid safety

37. Atazanavir EAP n Initiation, April 2002 (pending FDA comments) n Global program for patients in need n Entry criteria n Concomitant ARV agents n Data collection

38. Atazanavir EAP: eligibility n Absolute CD4 count < 300 cells/mm3 n Plasma HIV RNA > 5000 cp/ml n Unable to construct an alternate regimen - virologic failure or - intolerance n Refractory Treatment-related hyperlipidemia independent of - HIV RNA - CD4 count

39. Atazanavir EAP: Exclusions n Cardiac n Liver Enzymes n Need for certain ARV agents n Clinical and ECG criteria n ALT, bilirubin n Ritonavir, Kaletra, Indinavir, Efavirenz

40. Atazanavir EAP n Infrequent study visits n 2-month drug supply n Limited mandatory safety data collection - ALT, bilirubin - ECGs (2)

41. Atazanavir EAP n Study conduct through CRO (PPD) - North America Tel: 1 (877) - 726 - 7327 - Europe and Australia individual numbers by country PPD Brussels + 32 27232899